Cocaine abuse continues to present serious public health concerns. The last two decades has witnessed great advances in our understanding of the neurobiological basis of cocaine abuse. Yet, relatively little is known about neural adaptations which correspond to expression of the cocaine withdrawal syndrome. Using a cocaine self-administration paradigm to engage brain circuitry associated with human administration patterns, the present proposal aims to identify neural adaptations which correspond to the emergence of withdrawal symptoms during withdrawal. The first aim will be to assess behavioral depression as a model of cocaine withdrawal following repeated self-administration sessions. We will also determine the relationship between contingency and conditioned cues on the severity and duration of cocaine withdrawal. The second aim will be to use in vivo single-unit extracellular recording techniques to identify changes in the spontaneous activity, firing rates and bursting patterns of VTA Da neurons corresponding to behavioral disruptions during cocaine withdrawal. The third aim is to identify how changes in the activity of VTA DA neurons are mediated. We will use in vivo microiontophoresis to assess changes in the sensitivity of VTA DA neurons to DA, glutamate and GABA. Secondly, in vitro intracellular recording techniques will be used to assess changes in post-synaptic potentials evoked in VTA DA neurons. It is hypothesized that these studies will identify changes in the neuronal excitability of VTA DA neurons which correspond to behavioral cocaine withdrawal symptoms.